Drugs with a dopamine-like action, or an ability to block (antagonize) dopamine receptors are of therapeutic interest for a variety of reasons. First, it is known that certain dopamine-like substances may have utility as agents to control hypertension. Recently, two compounds SKF 38393 and SKF 82526 (Fenoldopam) have been clinically evaluated by Smith-Kline laboratories as novel antihypertensives. Both of those compounds are dopamine-like agents that act specifically at dopamine D-1 receptors. Presently none of the marketed antihypertensive agents work by this mechanism, but there is a great interest by the pharmaceutical industry in evaluating agents of this type for treatment of high blood pressure.
Parkinson's disease is a chronic, progressive disease that primarily affects older patients. It is characterized by an inability to control the voluntary motor system, and by an inability to initiate voluntary movements. Currently it is treated by giving L-DOPA, a precursor for dopamine in the central nervous system. In the later stages of the disease, it is treated by administering dopamine-like agents such as bromocriptine (Parlodel) marketed by Sandoz pharmaceuticals.
Schizophrenia is a severe mental disorder where patients are unable to function in society without treatment. They have delusions, hallucinations, and thought disorders that affect their perceptions of reality. Currently, schizophrenia is treated with chlorpormazine (Thorazine) or haloperidol (Haldol). These drugs block the acute hallucinations and severe thought disorders of schizophrenia, but leave the intellect of treated patients "blunted". Additional side effects produced by those drugs include a drug-induced Parkinson's syndrome, where voluntary movement is inhibited, and a long-term side effect known as tardive dyskinesia, which includes facial tics and uncontrollable lip and tongue movements. Thorazine has been the most widely used anti-schizophrenic agent and has been in use for more than 25 years. Both Thorazine and Haldol are believed to act by occupying dopamine receptors of the D-2 classification, but they do not elicit a dopamine-like response. Instead, these drugs are dopamine D-2 receptor blocking agents, or antagonists. Recently there has been great interest in developing drugs that will block another type of dopamine receptor, the dopamine D-1 receptor subtype. Great excitement was generated by the discovery that a compound known as SCH 23390, developed by Schering-Plough pharmaceuticals, was a specific dopamine D-1 receptor blocker. However, clinical trials with that drug failed due to toxicity problems. Thus far, no company has been able to develop a dopamine D-1 specific antagonist for evaluation as an antipsychotic agent.
The present invention provides novel compounds, designated generally as substituted trans-5,6,6a,7, 8, 12b-hexahydrobenzo[a]phenanthridines. The biological activities of the present compounds range from potent dopamine-like activity affecting both D-1 and D-2 dopamine receptor subtypes to specific dopamine D-1 receptor antagonist activity. They can be administered by oral or parenteral routes of administration in amounts effective to produce, for example, anti-hypertensive, anti-Parkinson or anti-psychotic responses.